{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T10:54:35Z","timestamp":1785236075105,"version":"3.55.0"},"reference-count":108,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T00:00:00Z","timestamp":1718323200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["EY031316"],"award-info":[{"award-number":["EY031316"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Human corneal fibrosis can lead to opacity and ultimately partial or complete vision loss. Currently, corneal transplantation is the only treatment for severe corneal fibrosis and comes with the risk of rejection and donor shortages. Sphingolipids (SPLs) are known to modulate fibrosis in various tissues and organs, including the cornea. We previously reported that SPLs are tightly related to both, transforming growth factor beta (TGF-\u03b2) signaling and corneal fibrogenesis. The aim of this study was to investigate the effects of sphingosine-1-phosphate (S1P) and S1P inhibition on specific TGF-\u03b2 and SPL family members in corneal fibrosis. Healthy human corneal fibroblasts (HCFs) were isolated and cultured in EMEM + FBS + VitC (construct medium) on 3D transwells for 4 weeks. The following treatments were prepared in a construct medium: 0.1 ng\/mL TGF-\u03b21 (\u03b21), 1 \u03bcM sphingosine-1-phosphate (S1P), and 5 \u03bcM Sphingosine kinase inhibitor 2 (I2). Five groups were tested: (1) control (no treatment); rescue groups; (2) \u03b21\/S1P; (3) \u03b21\/I2; prevention groups; (4) S1P\/\u03b21; and (5) I2\/\u03b21. Each treatment was administered for 2 weeks with one treatment and switched to another for 2 weeks. Using Western blot analysis, the 3D constructs were examined for the expression of fibrotic markers, SPL, and TGF-\u03b2 signaling pathway members. Scratch assays from 2D cultures were also utilized to evaluate cell migration We observed reduced fibrotic expression and inactivation of latent TGF-\u03b2 binding proteins (LTBPs), TGF-\u03b2 receptors, Suppressor of Mothers Against Decapentaplegic homologs (SMADs), and SPL signaling following treatment with I2 prevention and rescue compared to S1P prevention and rescue, respectively. Furthermore, we observed increased cell migration following stimulation with I2 prevention and rescue groups, with decreased cell migration following stimulation with S1P prevention and rescue groups after 12 h and 18 h post-scratch. We have demonstrated that I2 treatment reduced fibrosis and modulated the inactivation of LTBPs, TGF-\u03b2 receptors, SPLs, and the canonical downstream SMAD pathway. Further investigations are warranted in order to fully uncover the potential of utilizing SphK I2 as a novel therapy for corneal fibrosis.<\/jats:p>","DOI":"10.3390\/ijms25126560","type":"journal-article","created":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T08:52:10Z","timestamp":1718355130000},"page":"6560","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Amelioration of Fibrosis via S1P Inhibition Is Regulated by Inactivation of TGF-\u03b2 and SPL Pathways in the Human Cornea"],"prefix":"10.3390","volume":"25","author":[{"given":"Sarah E.","family":"Nicholas","sequence":"first","affiliation":[{"name":"North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"},{"name":"Department of Pharmaceutical Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandip K.","family":"Basu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4489-7748","authenticated-orcid":false,"given":"Nawajes","family":"Mandal","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN 38163, USA"},{"name":"Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8761-3824","authenticated-orcid":false,"given":"Dimitrios","family":"Karamichos","sequence":"additional","affiliation":[{"name":"North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"},{"name":"Department of Pharmaceutical Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"},{"name":"Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"107709","DOI":"10.1016\/j.exer.2019.107709","article-title":"Corneal injury: Clinical and molecular aspects","volume":"186","author":"Barrientez","year":"2019","journal-title":"Exp. 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